Lo studio Master Oncology. Davide Imberti MEDICINA INTERNA CENTRO EMOSTASI E TROMBOSI Ospedale G. da Saliceto PIACENZA

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1 Lo studio Master Oncology Davide Imberti MEDICINA INTERNA CENTRO EMOSTASI E TROMBOSI Ospedale G. da Saliceto PIACENZA

2 Relazioni con soggetti portatori di interessi commerciali in campo sanitario Ai sensi dell art. 3.3 sul Conflitto di Interessi, pag. 17 del Regolamento Applicativo dell Accordo Stato-Regione del 5 novembre 2009, dichiaro che negli ultimi due anni ho avuto i seguenti rapporti anche di finanziamento con soggetti portatori di interessi commerciali in campo sanitario: ABBOTT ALFA WASSERMANN BAYER BAXTER BOHERINGER INGELHEIM GSK KEDRION IL PFIZER SANOFI AVENTIS 2

3 Study Rationale (1) Venous thromboembolism (VTE) occurs commonly in patients with cancer, among whom it represents the second cause of death; moreover, VTE seems to have a negative influence on the outcome of these patients. However, the risk factors for VTE in cancer patients are only partially known 3

4 Study Rationale (2) In some retrospective analysis, carried out using population and hospital-based registries, it has been reported that patients with cancer and VTE have a worse survival than those with cancer without VTE 4

5 Study aim and design MASTER ONCOLOGY Prospective, multicenter, national, observational, non interventional, case-control study, specifically designed to identify VTE risk factors and to evaluate the influence of VTE on outcome of cancer patients with locally advanced or metastatic solid tumors 5

6 Coordinators: G. Agnelli - R. Labianca Steering Committee Adjudication Committee C. Cimminiello M. Moia - M. Mandalà L. Crinò G. Palareti G. Di Minno W. Ageno E. Maiello D. Imberti P. Prandoni D. Fagnani A. Santoro A. Falanga 6

7 Master Oncology Centers Alabiso - Novara Pinotti - Varese Artioli - Carpi Bertolini - Sondrio Lorusso - Lecce Caruso - Catania Quadri Bergamo Iacono Ragusa Massidda - Monserrato Cinieri - Brindisi Gebbia - Palermo Racca - Torino De Marinis - Roma Francini - Siena Masci - Rozzano Passalacqua - Cremona Tagliabue - Vimercate Daniele - Benevento Cavanna - Piacenza Comandone - Torino Verusio - Saronno Nardi - Reggio Calabria Crispino - Campostaggia Luppi - Modena Di Micco S. Giovanni Rotondo Palazzo - Cosenza Amoroso - Lido di Camaiore Bordonaro - Catania Scambia - Roma De Placido - Napoli Iacobelli - Chieti Clerico - Biella Ferrau - Taormina Di Costanzo - Firenze Gasparro - Parma Marsico - Napoli Testore - Asti Ciuffreda - Torino Corgna - Perugia Mattioli - Fano Carrozza - Campobasso Ardizzoia - Lecco Tabiadon - Milano Garufi - Roma Manzione - Potenza Aitini - Mantova Cognetti - Roma Fregoni - Pavia Gamucci - Sora Ficorella - L'Aquila Pastorelli - Padova 7

8 Study objectives Primary objective To identify the risk factors for thromboembolic events in patients with cancer Co-primary objective To evaluate the influence of the thromboembolic events on the outcome of cancer patients 8

9 Inclusion Criteria (1) Patients of both genders Age 18 years Patients who are referred to the Center with histologically proven solid tumors (lung, stomach, colon, pancreas, kidney, ovary, breast, prostate, other genitourinary), locally advanced or metastatic Life expectancy of more than 3 months Written informed consent given by patient for data collection prior to initiation of any study procedure 9

10 Inclusion Criteria (2) For the case group: objectively confirmed DVT or PE requiring treatment during any stage of the cancer disease Symptomatic DVT, confirmed by CUS or CT Symptomatic PE confirmed by lung scan, CT or pulmonary angiography Asymptomatic DVT, assessed by CUS or CT Asymptomatic PE detected by any diagnostic method 10

11 Exclusion Criteria Patients unable to fulfill the study follow-up program Surgery less than 2 months before study inclusion 11

12 Patients Case group: cancer patients (metastatic or locally advanced) referring to the Oncology Department with VTE diagnosis (within 1 month) Control group: for patients enrolled in the case group, matched control patients will be enrolled, on the basis of the following matching criteria case Age (+/- 5 yrs) Gender Cancer site Cancer histology Cancer stage control 12

13 Data collected Informed consent Inclusion/Exclusion criteria Demography ECOG performance status VTE characteristics Antithrombotic therapy Cancer characteristics Risk factors Concomitant therapy Survival at follow up Antineoplastic chemo or radiotherapy Hormonal therapy Antiangiogenetic therapy Past patient history of VTE Patient history of CV disease Recent trauma Severe comorbidities Immobility (>7 days) Growth factors CVC Venous chronic insufficiency Familiar VTE history (type) Known thrombophilia 13

14 Statistical power re-evaluation The study was discontinued in December 2009 due to difficulties in patients recruitment Before a decision about study discontinuation, a statistical power re-evaluation has been made, leading to the following conclusions: taking into account the first primary endpoint, assuming an exposure rate among controls = 0.20, a sample of 300 cases and 300 controls would be appropriate in order to appreciate, with α=0.05 and =0.10 [ =0.20], an odds ratio (OR) = 1.88 [OR=1.71] (an equivalent statistical power could be obtained also with, for example, 270/338 cases/controls) 14

15 Enrolled patients Survival data have been prospectively collected at 10 months and assessed through both Kaplan Meyer method and Cox proportional hazards regression From November 2008 to December 2009, 611 patients were enrolled in 51 Italian Oncology Centers (266 cases and 345 controls) Of these, 237 cases and 339 controls were evaluable 15

16 Patients characteristics Case Control Case Control Age (year) 64.7± ±8.7 Gender Female 135 (57.0) 197 (58.1) Male 102 (43.0) 142 (41.9) BMI (Kg/m 2 ) 25.3± ±4.3 ECOG Grade 0 94 (39.7) 198 (58.4) Grade (45.1) 114 (33.6) Grade 2 29 (12.2) 23 (6.8) Grade 3 7 (3.0) 2 (0.6) 16

17 Cancer site distribution 25 (4.3%) 12 (2.1%) 24 (4.2%) 122 (21.2%) 115 (20%) 36 (6.3%) 13 (2.3%) 38 (6.6%) 191 (33.2%) 17

18 Disease status 29 (5%) 547 (95%) 18

19 VTE diagnosis in the case group n (%) Symptomatic DVT 132 (55.7) Symptomatic PE 26 (11.0) Asymptomatic DVT 51 (21.5) Asymptomatic PE 53 (22.4) each patient can have one or more diagnosis specification 19

20 Risk factors analysis Case n (%) n=237 Control n (%) n=339 Adjusted Odds Ratio (95% CI) <23 71 (30.0) 127 (37.6) 1** BMI class (31.2) 115 (34.0) 1.16 ( ) (38.8) 96 (28.4) 2.06* ( ) Grade 0 94 (39.7) 198 (58.8) 1** ECOG Grade (45.1) 114 (33.8) 2.13* ( ) Grade (15.2) 25 (7.4) 2.96* ( ) Months from diagnosis >12 months 116 (48.9) 207 (61.1) 1** 12 months 121 (51.1) 132 (38.9) 1.97* ( ) Multiple logistic regression analysis *Statistically significant odds ratios. **Reference category BMI missing for 1 control patient - ECOG missing for 2 control patients 20

21 BMI, ECOG and months from diagnosis Attributable Risk (AR) Risk factor AR 95% CI BMI 20% 1.0%-39.1% ECOG 32.1% 19.8%-44.4% Months from diagnosis 19.8% 7.4%-32.3% BMI + ECOG 45.7% - BMI + Months from diagnosis 35.9% - ECOG + Months from diagnosis 45.6% - BMI + ECOG + Months from diagnosis 56.5% - 21

22 Probability of overall survival Overall survival Enrolled population (wilcoxon): (p<0.0001) Patients at Risk Control Case Control Case Events Total Follow-up (months) Mean survival (months) ,5 9,

23 Probability of overall survival Overall survival Evaluable population (wilcoxon): (p<0.0001) 0.25 Events Totals Control Case Patients at Risk Follow-up (months) Control Case

24 Multivariate survival Cox model Regressor: patient status, demographic data, anthropometric measures, tumor characteristics, info about therapies - Backward selection Parameter Patients status Any Analgesics Any Corticosteroids for systemic use Any other antineoplastic therapy Cancer site ECOG Parameter Estimate Chi-Square (p-value) Hazard Ratio (95% CI) Wald Chi-Square (p-value) Control 5.65* (0.0174) Case (0.0174) 1.36* ( ) No 11.19* (0.0008) Yes (0.0008) 1.64* ( ) No 3.89* (0.0486) Yes (0.0486) 1.29* ( ) No 3.97* (0.0464) Yes (0.0464) 1.65* ( ) Lung 15.19* (0.0017) Colon (0.0799) 0.74 ( ) Breast (0.0017) 0.53* ( ) Other cancer site (0.8520) 1.03 ( ) Grade * (<0.0001) Grade (0.0095) 1.45* ( ) Grade (<0.0001) 2.68* ( ) *Statistically significant hazard rations and Wald test 24

25 Probability of overall survival Overall survival Symptomatic/asymptomatic VTE vs control (enrolled population) (wilcoxon): (p<0.0001) Patients at Risk Cases (ASYMP.) Cases (SYMP.) Controls Events Totals Cases (ASYMP.) Cases (SYMP.) Controls Follow-up (months)

26 Conclusions (1) The study results highlight some risk factors for VTE (BMI, disease status and time from diagnosis), which are consistent with prior findings The data show that the concomitant presence of three factors - BMI >26, a more severe ECOG, and a time from diagnosis <12 months - account for 56% of VTE risk Although preliminary, our observations emphasize the need of better studying the incidence, the clinical profile and the potential risk factors for VTE in cancer patients 26

27 Conclusions (2) The study results demonstrate, for the first time, in a prospective and specifically designed study, that patients with cancer and VTE have a reduced survival compared to cancer patients without VTE These results are consistent for both symptomatic and asymptomatic patients 27